ABSTRACT Sporadic Alzheimer disease (sAD) is a neurodegenerative disorder that leads to acute memory and cognition loss in the elderly patients. An important characteristic of sAD is the diverse clinical sub-types that arise from different pathological phenotypes. Determining the molecular underpinnings of such clinical differences is important for diagnostic and therapeutic advances, but has remained a major challenge. Emerging evidence indicates that structural polymorphism within A? aggregates may cause the observed phenotypes in sAD. However, the relation between the neurotoxic, low molecular weight oligomers of amyloid- ? (A?) peptides and the observed phenotypes remains unclear. Results from our labs suggest that neurotoxic oligomers of A?42 formed in the presence of lipids (LDs) faithfully propagate their mesoscopic structure towards morphologically distinct fibrils and selectively induce vascular phenotype in transgenic AD mice. These results suggest that the distinct phenotypes can emerge from specific oligomer conformations, but also raise the question of whether LDs play a key catalytic role in generating distinct oligomer strains that manifest in pathology. We hypothesize that the physiochemical characteristics of LDs modulate A? aggregation to generate oligomer strains that propagate to elicit discrete phenotypes in the brain. The proposed research will focus on testing this hypothesis by determining the mechanistic understanding of LD-derived oligomer strains with three specific aims: Aim 1 we will focus on understanding the molecular mechanisms that dictate LD- induced oligomer strain generation; Aim 2 will focus on identifying the structures of LD-derived oligomers and how they relate to their propagation propensities, and Aim 3 will focus on determining how LD-oligomers induce phenotypes in mice brains. This project will involve a collaborative effort with biophysical and biochemical aspects investigated in the PI's lab, structural and mechanistic aspects in the Ramamoorthy lab (University of Michigan), molecular modeling work in the Hansmann lab (University of Oklahoma) and animal modeling work in the Levites lab (University of Florida). Together, the proposed research will generate critical insights into how phenotypes emanate from conformations of aggregates in sAD, and open new avenues for potential therapeutic interventions.